Abstract 2611: p63 constrains cancer cell transposable element expressions and viral mimicry response to sustain esophageal cancer development and indicates therapeutic vulnerability
Authors: Valen Zhuoyou Yu, Shan Shan So, Bryan Chee-Chad Lung, Carissa Wing-Yan Wong, Ian Yu-Hong Wong, Claudia Lai-Yin Wong, Desmond Kwan-Kit Chan, Fion Siu-Yin Chan, Betty Tsz-Ting Law, Ka-On Lam, Anthony Wing-Ip Lo, Josephine Mum-Yee Ko, Wei Dai, Alfred King-Yin Lam, Dora Lai-Wan Kwong, Simon Law, Maria Li Lung
Journal: Cancer Research (2023)

Abstract Background: Esophageal squamous cell carcinoma (ESCC) is the predominant form of esophageal cancer in developing areas and is among the top 10 deadliest cancers with a dismal 5-year survival rate of 10~20%. ESCC molecular pathogenesis has not been well characterized, while chemoradiotherapy remains the routine treatment option besides surgery, highlighting the need for a thorough understanding of ESCC and new treatment options. Tumor protein p63 (TP63), encoding p63, plays fundamental roles in stratified epithelial homeostasis. In the esophagus, ΔNp63 is the predominant isoform and is required for normal epithelial development. ESCC retains high ΔNp63 expression level, but its contribution to ESCC development is not fully understood. Results: We found ΔNp63 maintains ESCC development, depletion of which results in great attenuation and regression of cell line-derived xenograft growth in mice. Transcriptomic profiling showed type-I interferon (IFN-I) signaling-related pathways are the top pathways enriched in ΔNp63-depleted cells. This was further verified by quantitative PCR confirming up-regulations of interferon-stimulated genes upon ΔNp63 depletion in cell lines, and by transcriptomic profiling on our latest panel of naïve ESCC patient-derived organoids (PDOs) showing TP63 expression level negatively associated with IFN-I signaling-related pathways. Elevated endogenous retrotransposon-encoded RNA expression induces cancer cell IFN-I signaling through mediating tumor-suppressive viral mimicry response, an anti-viral state triggered by endogenous stimuli (1). We found cancer cell ΔNp63 depletion results in increased retrotransposon expression triggering dsRNA sensing and downstream signaling activation; Interferon regulatory factor 1 plays a critical role in mediating viral mimicry response downstream of ΔNp63. We further showed cells with lower ΔNp63 level and higher IFN-I signaling activity (ΔNp63-depleted cell lines and ΔNp63lo PDOs) display stronger responses to Decitabine, an anti-cancer drug and viral mimicry booster (1), as compared to control cell lines or ΔNp63hi PDOs, respectively. Conclusion: We identified a novel function of ΔNp63 in repressing cancer retrotransposon expression and explored the therapeutic potential of enhancing viral mimicry response, which may guide future ΔNp63/viral mimicry response-targeted therapy. Acknowledgement: We acknowledge the Research Grants Council (TRS T12-701/17-R to MLL) and the Food and Health Bureau (HMRF 06171566 to VZY) of Hong Kong SAR for funding supports. We acknowledge DSMZ for the KYSE cell lines. We acknowledge the HKUMed-CPOS for providing imaging facilities. Reference: 1.Chiappinelli KB, et al. Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses. Cell 2015 Citation Format: Valen Zhuoyou Yu, Shan Shan So, Bryan Chee-Chad Lung, Carissa Wing-Yan Wong, Ian Yu-Hong Wong, Claudia Lai-Yin Wong, Desmond Kwan-Kit Chan, Fion Siu-Yin Chan, Betty Tsz-Ting Law, Ka-On Lam, Anthony Wing-Ip Lo, Josephine Mum-Yee Ko, Wei Dai, Alfred King-Yin Lam, Dora Lai-Wan Kwong, Simon Law, Maria Li Lung. p63 constrains cancer cell transposable element expressions and viral mimicry response to sustain esophageal cancer development and indicates therapeutic vulnerability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2611.